It was found only a few years ago that reactive oxygen and nitrogen species (together abbreviated as reactive oxygen species=“ROS”) in addition to their non-directional mutagenic effect can also exert specific signal functions (Bauer et al., Chimica, 62, 1-9, 2008). The perception of said finding was especially complicated by the fact that by certain ROS quite often opposite biological effects can be caused.
EP 11170076.1 discloses that the inhibition of the protective membranous catalase of tumor cells results in a reactivation of the intracellular ROS signaling and thus, to the selective cell death of tumor cells. An inhibition of the protective catalase can also be achieved indirectly by the inhibition of a membranous SOD, since after the inhibition of the SOD the superoxide anions generated by the adjacent also membranous NADPH oxidase are no longer converted to H2O2. In this way, now there is present a sufficiently high local concentration of free superoxide anions that convert the active intermediate Compound I of the catalase (CATFeIV═O.+) to the inactive intermediate Compound II (CATFeIV═O) via a one-electron transfer and additionally convert active catalase (CATFeIII) to the inactive Compound III (CATFeIIIO2). By these two reactions the activity of the catalase is effectively inhibited (Kono Y and Fridovich I: Superoxide radical inhibits catalase. J Biol Chem 257:5751-5754, 1982. Shimizu N, Kobayashi K and Hayashi K: The reaction of superoxide radical with catalase. Mechanism of the inhibition of catalase by superoxide radical. J Biol Chem 259: 4414-4418, 1984).
However, for the role of ROS in the multi-stage oncogenesis nowadays a fairly clear picture can be drawn, the knowledge of which could show the way forward to the establishment of new selective tumor therapy methods (summarized in Bauer G. Tumor cell protective catalase as a novel target for rational therapeutic approaches based on specific intercellular ROS signaling. Anticancer Res. 32: 2599-2624, 2012; Bauer G. Targeting extracellular ROS signaling of tumor cells. Anticancer Res. 34: 1467-1482, 2014; Bauer G. Increasing the endogenous NO level causes catalase inactivation and reactivation of intercellular apoptosis signaling specifically in tumor cells. Redox Biol. 6: 353-371. 2015):    1) The mutagenic effect of ROS contributes to the classical step of “tumor initiation”.    2) ROS are of crucial importance for the step of “tumor promotion”, without the underlying mechanism being explained in detail. So, most of the known tumor promoters induce increased ROS levels and the specific scavenging of ROS inhibits the effect of most of the tumor promoters.    3) The malign transformation of cells regularly results in the expression of a membranous NADPH oxidase (NOX1). The continuous activity of this enzyme is of essential importance both for the proliferation of the malign cells and for maintaining the transformed state. NOX1 generates extracellular superoxide anions the dismutation product of which, H2O2, represents an autocrine proliferation stimulator for the cells.    4) However, the generation of extracellular superoxide anions also represents the basis for the formation of intracellular ROS controlled signal paths that selectively induce apoptosis of the transformed cells. Here, the “HOCl signal path” and the “NO/peroxynitrite signal path” that are explained in detail below are of particular importance.            Thus, the specific ROS dependent apoptosis induction in transformed cells is discussed as a potential elimination mechanism for malign cells.            5) A successful development of tumors requires that ROS producing malign cells protect themselves from the destructive effect of the ROS signal paths without thereby affecting the autocrine ROS production that is necessary for their proliferation. This results in the phenotype of tumor cells that is found regularly and in all tumor systems studied so far and that is characterized by a constitutive NOX1 activity and parallel activity of a membranous catalase. Additionally, a further modulation of the ROS signaling by membranous superoxide dismutase (SOD) takes place.    6) The selective inhibition of these membranous protective enzymes permits a ROS dependent selective apoptosis induction in tumor cells and thus, has great therapeutic potential.